Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

Abstract

Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated JNK signaling pathway upon paclitaxel treatment, we used cDNA microarrays to analyse the changes of gene expression in human ovarian cancer cells that were treated with paclitaxel and/or the JNK inhibitor SP600125. Among 20 genes that were specifically regulated by the paclitaxel-activated JNK pathway, interleukin (IL)-6 was shown to elicit function through the JAK-STAT signaling pathway in an autocrine and/or paracrine fashion. Subsequently, we identified that 87.5% of eight tested ovarian cancer lines secreted detectable levels of IL-6, which could be further upregulated 2-3.2 fold by 1 lM paclitaxel. Dissection on regulatory pathways for IL-6 indicated that (i) when ovarian cancer cells were treated with paclitaxel at low but clinically achievable concentrations (exemplified by 1 lM in this study), the JNK signaling pathway was the major stimulator of IL-6 gene regulation and (ii) at suprapharmacologically high concentrations (exemplified by 50 lM), paclitaxel exerted lipopolysaccharide-like effects, most likely through the Toll-like receptor 4 signaling pathway. Collectively, these results suggest that paclitaxel upregulates functional IL-6 expression in human ovarian cancer cells through multiple signaling pathways.

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

“…Both, JNK and p38 are crucial anti-survival factors in signaling cascades responding to inflammatory cytokines, UV light, cytotoxic drugs and diverse other pro-apoptotic stimuli [28,30,33]. Similarly to our experiments, these pathways were activated in the apoptotic response of various carcinoma cells following treatment with drugs such as Doxorubicin, Paclitaxel, Etoposide [34,35], Aplidin ™ [36], Tamoxifen [37] or Cisplatin (in human ovarian cancer cells) [38]. In the present study we show, by specific inhibition of the activity of p38 MAPK, that the apoptotic response of SKOV-3 ovarian cancer cells to 7Me-IEITC is strongly mediated by the p38 signaling pathway.…”

Toll‐like receptor‐4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel

“…9 In contrast, however, paclitaxel mediated LPS-like effects through the TLR4 signaling pathway in an ovarian cancer model. 33 In the present study we have shown for the first time that TLR4 knock-down using siRNA abolished the antiproliferative effects of paclitaxel in primary meningioma cell culture. These data indicate that in human meningiomas paclitaxel mediates a significant degree of its antiproliferative action via TLR4.…”

Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-β-activated kinase 1

“…Cell suspensions were filtered through a 40 mm filter and analysed for the cell cycle profile with the fluorescence activated cell sorting (FACS) Calibur flow cytometry system (BD, Biosciences, Franklin Lakes, NJ, USA) (Wang et al, 2006).…”